Lobular breast cancers differ both morphologically and clinically from the more common ductal type. They also differ in steroid hormone receptor expression and proliferation rates. Breast cancer cells demonstrating a lobular morphology may also be distinct with respect to allelic loss patterns and components of defined pathway, such as e- cadherin/catenin and BRCA1/BRCA2-mediated DNA repair. It has been difficult to assess the unique characteristics of lobular cancer most studies can only evaluate a small number of this relative uncommon tumor type. Over 350 tissue samples each of invasive lobular and ductal breast cancer will be collected and tested for expression of breast cancer- related proteins as part of an NCI-funded case-control study to assess associations between the use of combined hormone replacement therapy (CHRT) and the incidence of both invasive lobular and ductal breast cancer in women aged 55-79. Using the tissue samples collected in the study, we propose to 1) evaluate the difference in the rates of p53 allelic loss, mutation and protein over-expression in 350 each of invasive lobular and ductal cancers and 2) evaluate the difference in the genome- wide rate of allelic loss in 100 each of lobular and ductal cancers using newly developed microarray techniques (HuSNP). The large amount of data that is being carefully collected as part of the parent study will also allow us explore the contribution of alterations in BRCA-related DNA repair components and e-cadherin abnormalities to other tumor phenotypes such as ER and PR positive or negative subgroups. The genome-wide scan for LOH in a large set of lobular and ductal cancers will provide the most comprehensive description of allelic loss on lobular cancer to date. Information about morphology-specific traits gained from studying a large number of lobular cancers could lead to an increased understanding of the biology of distinct subsets of breast cancer, provide a basis for studies that would define patient stratification into prognostic and treatment groups and/or inform the development of targeted therapies for specific tumor types.